Genomic analysis of hepatic farnesoid X receptor binding sites reveals altered binding in obesity and direct gene repression by farnesoid X receptor in mice

Jiyoung Lee, Sunmi Seok, Pengfei Yu, Kyungsu Kim, Zachary Smith, Marcelo Rivas-Astroza, Sheng Zhong, Jongsook Kim Kemper

Resultado de la investigación: Contribución a una revistaArtículorevisión exhaustiva

55 Citas (Scopus)

Resumen

The nuclear bile acid receptor, farnesoid X receptor (FXR), is an important transcriptional regulator of liver metabolism. Despite recent advances in understanding its functions, how FXR regulates genomic targets and whether the transcriptional regulation by FXR is altered in obesity remain largely unknown. Here, we analyzed hepatic genome-wide binding sites of FXR in healthy and dietary obese mice by chromatin immunoprecipitation sequencing (ChIP-seq) analysis. A total of 15,263 and 5,272 FXR binding sites were identified in livers of healthy and obese mice, respectively, after a short 1-hour treatment with the synthetic FXR agonist, GW4064. Of these sites, 7,440 and 2,344 were detected uniquely in healthy and obese mice. FXR-binding sites were localized mostly in intergenic and intron regions at an inverted repeat 1 motif in both groups, but also clustered within 1 kilobase of transcription start sites. FXR-binding sites were detected near previously unknown target genes with novel functions, including diverse cellular signaling pathways, apoptosis, autophagy, hypoxia, inflammation, RNA processing, metabolism of amino acids, and transcriptional regulators. Further analyses of randomly selected genes from both healthy and obese mice suggested that more FXR-binding sites are likely functionally inactive in obesity. Surprisingly, occupancies of FXR, retinoid X receptor alpha, RNA polymerase II, and epigenetic gene activation and repression histone marks, and messenger RNA levels of genes examined, suggested that direct gene repression by agonist-activated FXR is common. Conclusion: Comparison of genomic FXR-binding sites in healthy and obese mice suggested that FXR transcriptional signaling is altered in dietary obese mice, which may underlie aberrant metabolism and liver function in obesity.

Idioma originalInglés
Páginas (desde-hasta)108-117
Número de páginas10
PublicaciónHepatology
Volumen56
N.º1
DOI
EstadoPublicada - jul. 2012
Publicado de forma externa

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